doi: 10.1161/01.RES.0000033472.61704.CE
© 2002 American Heart Association, Inc.
Editorials |
PPAR
and Vascular Inflammation
Adding Another Piece to the Puzzle
From the Department of Internal Medicine II, Cardiology, University of Ulm, Germany.
Correspondence to Nikolaus Marx, MD, Dept of Internal Medicine II, Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}medizin.uni-ulm.de
Key Words: arteriosclerosis • peroxisome proliferator-activated receptor 
• CCAAT/enhancer-binding protein • inflammation • vascular smooth muscle cells
Work in basic science and clinical research over the last decades has led to our present understanding of arteriosclerosis as an inflammatory disease in the vessel wall. As such, lesion development is characterized by the presence of inflammatory cells like monocytes and T cells, the release of proinflammatory cytokines like interleukin (IL)-6 and tumor necrosis factor (TNF), as well as by the activation of vascular smooth muscle cells (VSMCs).1 This inflammatory environment can ultimately result in unstable, vulnerable lesions, which are prone to rupture, thus potentially causing acute coronary syndromes.2 Given the present view of atherogenesis, research in vascular biology has focussed on strategies to modulate this inflammatory process in the vessel wall. Among those approaches, activators of the ligand-activated nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) have emerged as a promising tool to influence inflammation in the vasculature. Originally identified as master regulators in adipogenesis and glucose homeostasis (reviewed in Auwerx3), work from the last couple of years has shown that PPAR is expressed in vascular cells in vivo and in vitro, and that activators of PPAR may exhibit antiinflammatory properties in these cells. In monocytes/macrophages, PPAR activators inhibit the release of proinflammatory cytokines and matrix-degrading enzymes; in endothelial cells, they modulate the expression of chemokines and endothelin; and in T cells, PPAR ligands have been shown to reduce the secretion of IFN-. Moreover, in VSMCs, PPAR inhibits migration and proliferation and decreases the release of matrix metalloproteinases. In vivo experiments in mouse models of arteriosclerosis as well as studies in rats bolstered the hypothesis of PPAR being a modulator of the inflammatory response in the vessel wall by showing reduced lesion size and restenosis upon PPAR stimulation (reviewed in Marx4). Because PPAR can be activated by the novel group of clinically used antidiabetic thiazolidinediones (TZDs, glitazones),5 like troglitazone, rosiglitazone, and pioglitazone, this concept seemed not only of interest for basic scientists, but rather attracted clinicians, especially those treating patients with diabetic mellitus. Early clinical data revealed a reduction of inflammatory serum markers of arteriosclerosis6 as well as a reduction of intima-media thickness upon TZD treatment in diabetic patients,7 leading to the initiation of large clinical trials, presently investigating the effect of TZDs on cardiovascular mortality in this population of high-risk patients.
Despite the rapid evolvement of the PPAR field from bench to bedside, many questions remain open concerning the molecular mechanisms underlying the antiinflammatory properties of PPAR in vascular cells. The work from Takata and colleagues8 in this issue of Circulation Research significantly contributes to this area by elaborating the interaction of PPAR with the proinflammatory transcription factor CCAAT/enhancer-binding protein-
(C/EBP-). C/EBP- is a known mediator of inflammatory gene expression in vascular cells, eg, with regulatory effects on the expression of IL-6, IL-1ß, and TNF-
. Using an animal model of balloon injury in rats, the authors demonstrate that both PPAR as well as C/EBP- are upregulated in injured vessels compared to controls. They further show that overexpression of C/EBP- in VSMCs increases PPAR protein expression and promoter activity, suggesting that the proinflammatory transcription factor C/EBP- enhances PPAR expression via two C/EBP binding sites in the PPAR promoter. Activation of PPAR by TZDs then in turn decreased C/EBP- promoter activity and expression, thus, in conjunction with an inhibition of nuclear factor-
B (NF-B), leading to a reduction of IL-1ß–induced IL-6 release. Previous work in vascular cells has shown that PPAR counterbalances the activity of the proinflammatory transcription factors NFB, AP-1, and STAT, all considered to be involved in atherogenesis.9 Takata and colleagues extent this list by demonstrating PPAR effects on C/EBP-, suggesting that PPAR does not only inhibit C/EBP- expression, but may also limit the cooperative interaction between C/EBP- and NF-B.
Putting their data into a larger perspective, Takata et al8 propose a novel model of inflammatory homeostasis in the vessel wall: vascular inflammation induces C/EBP-, which then transactivates proinflammatory target genes like TNF- and IL-6 on one hand, as well as the antiinflammatory PPAR gene on the other hand. The induced proinflammatory mediators then furnish vascular inflammation by enhancing C/EBP- expression, whereas activation of PPAR should result in a negative feedback on C/EBP- induction, thus limiting the inflammatory process in the vessel wall. This concept is very intriguing because the PPAR-activating TZDs would exhibit the strongest antiinflammatory effect where it is needed the most—in the inflamed vasculature, where PPAR is upregulated. Still, given that nature did probably not invent PPAR to be only stimulated with TZDs by physicians and scientists, a key player in the puzzle is missing—the natural occurring ligand present in the lesion. Previous work has established 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) as such a natural PPAR ligand10 and Takata and colleagues demonstrate that 15d-PGJ2 can also inhibit C/EBP- in VSMCs, but is 15d-PGJ2 the master activator of PPAR in the vessel wall? J2 prostanoids, the immediate upstream precursors of 15d-PGJ2, are found in vivo and are all derived from PGD2. The PGD2-producing enzyme, PGD2-synthase, is expressed in macrophages and antigen-presenting cells,11 and may thus be detectable in the plaque, but it is unclear if 15d-PGJ2 itself is present and of relevance in arteriosclerotic lesions. Others discovered oxidized linoleic acid (9- and 13S-HODE), components of oxidized low-density lipoprotein, as naturally occurring ligands for PPAR. However, it has been suggested that these activators promote foam cell formation from monocytes, thus potentially exhibiting proatherogenic effects in vascular cells.12,13 May these forms of oxidized linoleic acid also inhibit C/EBP- and NF-B in the vessel wall?
To date, PPAR seems a good candidate to counterbalance the action of proinflammatory transcription factors in atherogenesis and the work of Takata and colleagues extends and strengthens the hypothesis of PPAR being a "good guy" in the vessel wall. Still, further studies will have to identify the naturally occurring ligands in the lesion to finally close the loop of negative and positive feedback in vascular inflammation. Nevertheless, the effects of PPAR-activating, antidiabetic TZDs in this context are very promising and may broaden our understanding of the biological action of these substances. In addition to their metabolic effects, TZDs seem to inhibit other transcription factors in vascular cells and may thus exhibit local antiinflammatory properties in the vasculature. We have to await the results of current clinical trials to see whether such TZD effects might affect the clinical course of arteriosclerosis and potentially influence cardiovascular mortality in treated patients. In the meantime, we should try to better understand the molecular mechanisms of PPAR activation in the vessel wall and add other pieces to the puzzle of PPAR and vascular inflammation.
Acknowledgments
This work was supported by grants of the Deutsche Forschungsgemeinschaft (MA 2047/2-2, SFB 451, Project B9) and the Else-Kröner-Fresenius-Stiftung to Dr Nikolaus Marx.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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